The incidence of obesity in the general population of the United States has shown a dramatic increase over the last decade with over 50% of the population considered overweight or obese. A similar trend is observed in other countries as the so-called Western diet is adopted. Since obesity is associated with a variety of co-morbidities such as diabetes, hypertension, and atherosclerosis, this increase is a major health concern.
A number of approaches have been proposed or used to help subjects reduce food intake, otherwise referred to as energy intake, and thereby manage their body weight. These approaches include use of agents to act on the central nervous system to increase levels of serotonin, and those acting in the gastrointestinal tract to reduce digestion and/or absorption of nutrients. These approaches suffer from potential side effects that reduce their utility for long-term body weight management.
A different approach involves the introduction of nutrients directly into the distal small intestine in an attempt to reduce concomitant food intake. This approach uses natural materials and is believed to function via interactions of the nutrients with putative receptors throughout the small intestine, particularly in the distal small intestine (jejunum, ileum) that are believed to participate in the natural mechanisms that induce termination of a meal. This offers the potential advantage of a reduction of side effects due to the use of natural materials and mechanism. Reported data in animals and humans are based on using catheters and naso-gastric tubes respectively, to directly introduce nutrients into their small intestines. Many of the reported studies have employed lipids. For example, infusion of a corn oil emulsion into the small intestine (jejunum or ileum) reduces food intake at a concomitant meal such that total caloric intake (meal plus infusate) is significantly or directionally reduced; see I. Welch, K. Saunders and N. W. Read, Effect of Ileal and Intravenous Infusions of Fat Emulsions on Feeding and Satiety in Human Volunteers, Gastroenterology 89: 1293-1297, 1985; I. Welch, C. P. Sepple and N. W. Read, Comparisons of the Effects on Satiety and Eating Behavior of Infusion of Lipid into the Different Regions of the Small Intestine, Gut 29: 306-311, 1988; all incorporated herein by reference. Intravenous administration of a triacylglycerol emulsion (Intralipid) failed to reduce total caloric intake in several studies; see I. Welch, K. Saunders and N. W. Read, id.; E. K. Walls and H. S. Koopmans, Effect of Intravenous Nutrient Infusions on Food Intake in Rats, Physiiology & Behavior 45: 1223-1226, 1989; all incorporated herein by reference. Pre-meals of triacylglycerol in yogurt also fail to reduce total caloric intake (meal plus pre-meal) at a subsequent meal; see B. J. Rolls, S. Kim, A. L. McNelis, M. W. Fischman, R. W. Foltin, and T. H. Moran, Time Course of Effects of Preloads High in Fat or Carbohydrate on Food Intake and Hunger Ratings in Humans, Am. Journl. Physiology, 260: R756-R763, 1991; J. H. Meyer, M. Hlinka, A. Khatibi and H. E. Raybould, Role of Small Intestine in Caloric Compensations to Oil Premeals in Rats, Am. Journl. Physiology, 275: R1320-R1333, 1998; all incorporated herein by reference.
There are many animal studies where nutrients are infused into the small intestine to reduce food intake. For example, Woltman et al. have shown that micellar solutions of oleate infused into the duodenum reduced 4-hour food intake in rats to a greater extent than a micellar triolein solution and that duodenal infusion is more potent than ileal infusion in reducing food intake; see T. Woltman and R. Reidelberger, Effects of Duodenal and Distal Ileal Infusions of Glucose and Oleic Acid on Meal Patterns in Rats, Am. Journl. Physiology, 269: R7-R14, 1995; T. Woltman, D. Castellanos and R. Reidelberger, Role of Cholecystokinin in the Anorexia Produced by Duodenal Delivery of Oleic Acid in Rats, Am. Journl. Physiology, 269 R1420-R1433, 1995; all incorporated herein by reference. Greenberg et al have shown that duodenally infused emulsions of triacylglycerol and linoleic acid reduce total caloric intake in a sham feeding rat model, whereas ileal infusions do not; see D. Greenberg, G. P. Smith and J. Gibbs, Intraduodenal Infusions of Fats Elicit Satiety in Sham Feeding Rats, Am. Journl. Physiology, 259: R110-R118, 1990; D. Greenberg, G. P. Smith and J. Gibbs, Intravenous Triglycerdies Fail to Elicit Satiety in Sham-Feeding Rats Am. Journl. Physiology, 264: R409-R413, 1993; D. Greenberg, Fats and Satiety: the Role of the Small Intestine, Appetite 31: 229, 1998; D. Greenberg, Intestinal Satiety, in Satiation from Gut to Brain, G. P. Smith (ed.), pp. 40-70, Oxford University Press, Inc., New York, N.Y., 1998; all incorporated herein by reference. Other long chain fatty acids (oleic, linolenic) were somewhat less effective.
Meyer et al. have conducted a series of studies investigating the effects of infused nutrients upon total caloric intake in rats constrained to three hours of feeding. They found that emulsions of fatty acids greater than 10 carbons in length, solutions of monomeric carbohydrates only with affinity for the glucose transporter, and solutions of the amino acids tryptophan and phenylalanine suppressed total caloric intake when infused in the duodenum or mid-gut (jejunum), or into the colon. These investigators also demonstrated that pre-meals of triacylglycerol failed to suppress total caloric intake in rats constrained to seven hours of feeding; see J. H. Meyer, M. Hlinka, Y. Tabrizi, N. DiMaso and H. E. Raybould, Chemical Specificities and Intestinal Distributions of Nutrient-Driven Satiety, Am. Journl. Physiology, 275: R1293-R1307, 1998; J. H. Meyer, Y. Tabrizi, N. DiMaso, M. Hlinka and H. E. Raybould, Length of Intestinal Contact on Nutrient-Driven Satiety, Journl. Physiology, 275: R1308-R1319, 1998; all incorporated herein by reference.
More recently, Cox et al. have shown that jejunally infused neat linoleic acid or oleic acid (0.2 mL/hr for seven hours) will significantly reduce total daily caloric intake in rats, whereas a long chain triacylglycerol (corn oil) will not. These authors also demonstrated that the reduction is maintained over 20 days of dosing, resulting in a significant difference in weight between treated and control animals; see J. E. Cox, W. J. Tyler, A. Randich, G. R. Kelm, S. S. Bharaj, R. J. Jandacek and S. T. Meller, Suppression of Food Intake, Body Weight, and Body Fat by Jejunal Fatty Acid Infusions, Am. Jourl. Physiology, Regulatory Integrative Comparative Physiology, 278: R604-R610, 2000; all incorporated herein by reference.
There are no reported studies known to the inventors in which ingested or gastrically administered nutrients in a pharmaceutical dosage form designed to release the nutrients in the small intestine have been used to reduce food intake. PCT Application WO 87/03198, U.S. Pat. Nos. 5,322,697, and 5,753,253 disclose using such pharmaceutical preparations for reduction of food intake; all incorporated herein by reference. Infusion data are provided to support these disclosures However, no data are provided that are derived from the use of enteric nutrient dosage forms designed to release in the small intestine for reducing food consumption and total caloric intake.
Body weight management methods employing natural nutrients to reduce food intake through natural mechanisms are highly sought after. A need still exists for a product comprising nutrient materials that can be ingested by human and animal subjects to reduce consumption of food and lower the total daily caloric intake of the subject